Genetics of Congenital Heart Disease

1. Genetics of Congenital Heart Disease 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: C303, Teaching Building 2016/03

2. Required Reading 1. Thompson &Thompson Genetics in Medicine, 8th ed. 2016 ● Pages 80-82、141-142、354 2. Moran R, Robin NH. Congenital Heart Defects. In: Emery and Rimoin's Essential Medical Genetics. Academic Press, 2013. pp.169-174

3. Learning Objectives To recognize familial patterns of CHD To understand developmental mechanisms of CHD To see CHDs as examples of the larger group of common disorders with common complex inheritance involving Single genes Multiple genes Environmental influences

4. Introduction to CHD Relatively common birth defect Liveborn infants ~8/1 000 (the most common birth defect worldwide, the most common cause of birth defect-related death) Stillborns 10× higher or 8% Miscarriages 15% in abortuses <24 weeks gestation

5. Introduction to CHD Variety of causes Single gene Chromosomal Multiple genes Teratogen exposures致畸剂暴露 Maternal rubella (风疹) infection Gestational diabetes mellitus妊娠糖尿病

8. Gross Chromosomal Defects 5-8% of Defects Examples Trisomy 21: 35-50% Trisomy 18: 99% Turner syndrome: 20% Single-Gene Defects 3% of Defects Genetic Component

9. Developmental Mechanisms Flow Lesions Problems in Cell Migration Problems in Cell Death Abnormalities in Extracellular Matrix Abnormalities in Targeted Growth

20. Flow Lesions流动性病变 Large category of CHDs Approximately 50% of all CHDs Up to 25% of flow lesion CHDs, particularly tetralogy of Fallot, have del22q11.2 DiGeorge syndrome Velocardiofacial syndrome（软腭-心-面综合征） Conotruncal anomaly face syndrome（圆锥动脉干异常面容综合征）

21. del22q11.2 Syndromes Autosomal dominant Variable expressivity Deletion of approximately 3Mb Caused by homologous recombination of low copy repeat sequences One of the most common cytogenetic deletions with a significant phenotype 1/2000-4000 live births

22. 22q11.2 Rearrangements

23. del22q11.2 Syndromes Phenotypes may include CHD Craniofacial abnormalities颅面骨畸形 Intellectual disability/developmental delay Reduced circulating lymphocytes Hypocalcemia（低钙血症） Schizophrenia（精神分裂症）

24. del22q11.2 and CHD Responsible for 5%-12.5% CHDs Particularly common in certain CHDs >40% of patients with tetralogy of Fallot (TOF) and pulmonary atresia（肺动脉瓣闭锁） >60% of patients with TOF and absent pulmonary valve

25. Features Include: Cardiac: Conotruncal Defects Immunologic: Thymic Aplasia不发育 or Hypoplasia发育不全 Hypocalcemia: Parathyroid Absence or Hypoplasia（发育不全） Dysmorphism: Hypertelorism（器官间距过远）, Short Philtrum（人中）,Cupid’s Bow Mouth, Ear Anomalies DiGeorge Syndrome

26. Features Include: Cardiac: VSD, Tetralogy of Fallot, Rt. Aortic Arch Cleft Palate: Overt or Submucosal Development Delay: Mild-to-Moderate, esp. Speech Dysmorphisms: Prominent Nose, Abnormal Ears, Abundant Hair, Tapered Fingers VeloCardioFacial (VCF) Syndrome

27. VCF/DG SYNDROMESClinical Overlap Cleft Palate Dev. Delay VCF Facies Cleft Palate Dev. Delay DGS CHD Dev. Delay VCF Facies

29. Cardiac GeneticsPopulation Perspective Developing Innovative Therapies Postnatal Interventions Marfan Syndrome: Anti-TGF Prenatal Interventions Folate Improving Clinical Trials Research Cardiology Emulating Heme/Onc Primary Endpoints - Function, Not Survival Better Statistical Power

31. Familial Patterns of Recurrence CHD recurrence in a family Affected individuals may not have identical anatomical heart abnormality Will have lesions representing similarity in the developmental mechanism Should look for abnormalities outside of the cardiovascular system May indicate a syndromic association with CHD

34. First, exome-centered and whole-genome next-generation sequencing • Second, epigenetics and transcriptomics • Third, systems biology

35. Epigenetics and Transcriptomics • Research is increasingly acknowledging that static DNA sequence variation explains only a fraction of the inherited phenotype. Therefore, we expect that multiple epigenetic and gene expression signatures will be related to CVD in experimental and clinical settings.

36. Complex relationships between the genome, epigenetic and transcriptional regulations, the proteome, and the metabolome that produce CVD phenotypes.